Biology subjects

Kilian, M.

Publications and source records attributed to Kilian, M..

3 recordsLinked to original sources

bioRxiv2025

Conserved programs and specificities of T cells targeting hematological malignancies

T cell-mediated immune surveillance is critical for cancer control, yet its endogenous effectiveness in hematological malignancies remains limited and poorly understood. Here, we integrate single-cell T cell receptor (TCR) profiling, HLA immunopeptidomics and functional antigen mapping to dissect the specificity landscape of bone marrow lymphocytes (BMLs) in multiple myeloma (MM) and acute myeloid leukemia (AML). We identify a rare subset of tumor-reactive T cells that exhibit a stereotyped transcriptional state distinct from bystander and virus-specific populations. Across both malignancies, immunopeptidomic profiling uncovers a partially conserved antigen repertoire enriched for noncanonical peptides, including products of novel or unannotated open reading frames (nuORFs), pseudogenes, and clonotypic immunoglobulin sequences. Several of these epitopes are recurrently presented and associated with convergent TCR responses across individuals. Based on this immune architecture, we develop a TCR-intrinsic fitness model that infers BML tumor specificity from transcriptional cues and stratifies immunotherapy response across three independent patient cohorts. Together, these findings map the latent potential of endogenous anti-tumor immunity in two biologically distinct diseases and provide a framework for decoding and restoring productive immune surveillance of hematological malignancies. HighlightsO_LISingle-cell resolved TCR profiling maps rare tumor-reactive T cells in the bone marrow of multiple myeloma (MM) and acute myeloid leukemia (AML) reveals conserved transcriptional programs C_LIO_LIA shared immunopeptidome across MM and AML includes noncanonical epitopes from nuORFs and idiotype sequences C_LIO_LIConserved tumor antigens elicit convergent T cell responses across patients C_LI O_LIA TCR fitness model predicts tumor specificity in bone marrow lymphocytes and stratifies immunotherapy response in both hematological malignancies C_LI

immunology↗

bioRxiv2022

MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors

Cancer immunotherapy critically depends on fitness of cytotoxic and helper T cell responses. Dysfunctional cytotoxic T cell states in the tumor microenvironment (TME) are a major cause of resistance to immunotherapy. Intratumoral myeloid cells, particularly blood-borne myeloids (bbm), are key drivers of T cell dysfunction in the TME. We show here that major histocompatibility complex (MHC) class II (MHCII)-restricted antigen presentation on bbm is essential to control the growth of brain tumors. Loss of MHCII on bbm drives dysfunctional intratumoral tumor-reactive CD8+ T cell states through increased chromatin accessibility and expression of Tox, a critical regulator of T cell exhaustion. Mechanistically, MHCII-dependent activation of CD4+ T cells restricts myeloid-derived osteopontin that triggers a chronic activation of nuclear factor of activated T cells (Nfat)2 in tumor-reactive CD8+ T cells. In summary, we provide evidence that MHCII-restricted antigen presentation on bbm is a key mechanism to directly maintain functional cytotoxic T cell states in brain tumors. Highlights- MHCII on intratumoral blood-borne myeloid cells is required for sustained anti-glioma T cell response - Loss of myeloid MHCII drives dysfunction of CD8+ T cells by activating TOX - Tox expression is induced by osteopontin-triggered chronic NFAT2 signaling in tumor-reactive CD8+ T cells - steopontin production is restricted upon intratumoral T helper cell activation via MHCII - MHCII expression on tumor-infiltrating bbm correlates with osteopontin expression and cytotoxic T cell dysfunction in human glioblastoma tissue O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/495502v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@1fbedc7org.highwire.dtl.DTLVardef@b7dc3aorg.highwire.dtl.DTLVardef@db7fe6org.highwire.dtl.DTLVardef@aa06b7_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2019

Investigating the biochemical properties of Streptococcal polysaccharide capsules using atomic force microscopy

In common with many bacterial pathogens, Streptococcus pneumoniae has a polysaccharide capsule, which facilitates immune evasion and is a key virulence determinant. However, recent data has shown that the closely related Streptococcus mitis can also express polysaccharide capsules including those with an identical chemical structure to S. pneumoniae capsular serotypes. We have used atomic force microscopy (AFM) techniques to investigate the biophysical properties of S. mitis and S. pneumoniae strains expressing the same capsular serotypes that might relate to their differences in virulence potential. When comparing S. mitis and S. pneumoniae strains with identical capsule serotypes S. mitis strains were more susceptible to neutrophil killing and imaging using electron microscopy and AFM demonstrated significant morphological differences. Force-volume mapping using AFM showed distinct force-curve profiles for the centre and edge areas of encapsulated S. pneumoniae and S. mitis strains. This \"edge effect\" was not observed in the unencapsulated streptococcal strains and in an unencapsulated Staphylococcus aureus strain, and therefore was a direct representation of the mechanical properties of the bacterial capsule. When two strains of S. mitis and S. pneumoniae expressed an identical capsular serotype, they presented also similar biomechanical characteristics. This would infer a potential relationship between capsule biochemistry and nanomechanics, independent of the bacterial strains. Overall, AFM was an effective tool to explore the biophysical properties of bacterial capsules of living bacteria by reproducibly quantifying the elastic and adhesive properties of bacterial cell surfaces. Using AFM to investigate capsule differences over a wider range of strains and capsular serotypes of streptococci and correlate the data with phenotypic differences will elucidate how the biophysical properties of the capsule can influence its biological role during infection.

microbiology↗